New Study Explains How Some Cancers Survive Histone Deacetylase Inhibitor Treatment

Histone deacetylase inhibitors exert their anti-tumor effects via the induction of expression changes of oncogenes or tumor suppressors, through modulating the acetylation/deactylation of histones and/or non-histone proteins such as transcription factors.

Vorinostat (suberoylanilide hydroxamic acid), the most widely used HDACi, has been shown to bind to the active site of histone deacetylases and act as a chelator for zinc ions also found in the active site of histone deacetylases. Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.

HDAC inhibitors can successfully treat certain types of cancer, such as lymphoma, but other types survive this disruption. Investigators at Cancer Research, United Kingdom (London) and the University of Birmingham (United Kingdom) now believe that they have unraveled the reason why HDACi is surprisingly well tolerated by most eukaryotic cells.

They reported in the September 16, 2015, online edition of the journal Epigenetics and Chromatin that they had used high density microarrays to observe dynamic changes in transcript levels that appeared during the first two hours of exposure of cancer cultures to HDACi. There was a consistent response to two different inhibitors at several concentrations. Components of all known lysine acetyltransferase (KAT) complexes were down-regulated, as were genes required for growth and maintenance of the lymphoid phenotype. Up-regulated gene clusters were enriched in regulators of transcription, development, and phenotypic change.

First author Dr. John Halsall, a postdoctoral research fellow at the University of Birmingham, said, "Our work has shown that some cancer cells can survive the gene damage caused by HDAC inhibitor drugs, so we have unveiled a new layer of the cancer cell's defense that we need to target to destroy tumors. If we work out exactly which types of cancer are vulnerable to these drugs we can use them in a smarter way to treat patients more effectively."

Dr. Kat Arney, science information manager at Cancer Research, United Kingdom, said, "Working out how genes are switched on and off in cancer is vital if we are to truly understand and beat the disease. This study could help us tailor how we use HDAC inhibitors so that more patients could benefit from them, and we will continue to work towards finding more effective ways to target cancer's control mechanisms in the future."

Related Links:
Cancer Research, United Kingdom
University of Birmingham